As the population continues to age, cognitive decline and dementia are becoming increasingly important public health issues. While Alzheimer's disease is the most common cause of dementia, it is becoming increasingly evident that cerebrovascular mechanisms underlie cognitive impairment with mixed pathology accounting for at least half of all dementia cases. A majority of clinical research linking cerebrovascular mechanisms to cognitive impairment has focused on neuroimaging evidence of small vessel disease, such as white matter hyperintensities (WMHs) and silent lacunar infarcts. Less attention has been given to serum or cerebrospinal fluid (CSF) biomarkers that may be precursors to overt cerebrovascular disease evidence on neuroimaging. We propose to leverage an existing local cohort, the Vanderbilt Memory & Aging Project, to examine noninvasive serum and CSF biomarkers in relation to cognitive functioning and neuroimaging markers of small vessel disease, white matter integrity, and microcirculation in older adults. Since the Vanderbilt Memory & Aging Project cohort's inception in 2012, we have completed serial visits (baseline, 18-months, 36-months) with key covariate ascertainment, neuropsychological assessment, multimodal 3T brain MRI, and fasting blood and CSF acquisition, including maintaining a biosample repository on older adults free of clinical stroke and dementia at enrollment. Thus, we are very well positioned to examine proteomic serum and CSF biomarkers in relation to cross-sectional and longitudinal neuroimaging and cognitive outcomes. Results from this collaborative effort will provide a dynamic understanding of axonal injury, amyloid deposition, tau aggregation, and neurodegeneration associations with small vessel disease, white matter integrity, and microcirculatory health. Results will yield important applications for investigations examining the natural history, analytic epidemiology, prevention, clinical diagnosis, prognosis, and disease management of age-related and pathological changes in small vessel, white matter, and microcirculatory health.